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Keywords:

  • orofacial diseases;
  • immunomodulatory agents;
  • calcineurin inhibitors;
  • thalidomide;
  • dapsone;
  • colchicine;
  • cyclophosphamide

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Systemic non-biologic agents have long been in clinical use in medicine – often with considerable efficacy, albeit with some adverse effects – as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non-biologic agents (NBAs) include a range of agents, most importantly the corticosteroids (steroids). Previous articles by us in this series have discussed systemic use of corticosteroids and purine synthesis inhibitors; the other immunomodulating agents (calcineurin inhibitors, thalidomide, dapsone, colchicine and cyclophosphamide) are reviewed in this final article.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Some agents are not regarded as classical immunosuppressants, rather as immunomodulatory agents. Among these agents that are used in oral diseases are calcineurin inhibitors, thalidomide, dapsone, colchicine and cyclophosphamide. These agents are reviewed here.

Calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

The calcineurin inhibitors, namely ciclosporin and tacrolimus, are among the most popularly used systemic immunosuppressive agents – especially for transplant patients (Table 1).

Table 1. Calcineurin inhibitors: characteristics and main clinical applications in oral diseases
DrugFDA indicationsInteractionsSide effects (common)DosagesOral diseasesPrice/unit
  1. EBA, epidermolysis bullosa acquisita; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis; GVHD, graft-versus-host disease.

CiclosporinProphylaxis of organ rejection in patients receiving allogeneic kidney, liver or heart transplants, rheumatoid arthritis, psoriasis

Antibiotics

Anti-fungals

Calcium channel blockers

Grapefruit

Hepatotoxicity

Hypertension

Hypertrichosis

Nephrotoxicity

Typical starting dose for psoriasis: 2–5 mg kg−1 per day

Oral lichen planus

Oral pemphigus vulgaris EBA

SJS and TEN

Chronic GVHD

$350–560/for 100 capsules of 100 mg
TacrolimusProphylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants

Aminoglycosides

Amphotericin

Calcium channel blockers

Cisplatin

Grapefruit juice

Protease Inhibitors

Hyperglycaemia Hypertension

Nephrotoxicity

Neurotoxicity

0.2 mg kg−1 per day as initial dose followed by taperingPemphigus vulgaris$300–370/for 100 capsules of 1 mg

Ciclosporin

Ciclosporin (alternative name cyclosporine) is a peptide from the fungus Tolypocladium inflatum, which was originally synthesized as an antifungal agent and is chemically related to the macrolide antimicrobial family (Tedesco and Haragsim, 2012). The immunosuppressive properties of ciclosporin were recognized early on, and ciclosporin revolutionized the survival of transplant patients (Tedesco and Haragsim, 2012). The agent has also received approval for use in several T-cell-mediated dermatoses (Madan and Griffiths, 2007).

Ciclosporin binds with the intracytoplasmic protein immunophilin in target cells where the ciclosporin–immunophilin complex inhibits calcineurin, a phosphatase required for the activation of the factor NF-AT (nuclear factor of activated T cells). NF-AT, a transcription factor specific for T lymphocytes, translocates to the nucleus where it binds in the promoter region of genes responsible for the synthesis of inflammatory cytokines – including some interleukins (IL-2, IL-4), transforming growth factor-beta, interferon-γ (INFγ) and tumour necrosis factor (TNF).

Tacrolimus

Tacrolimus is a macrolide, but has no significant antimicrobial effects (Jacobson et al, 1998). The immunosuppressive mechanism of tacrolimus is similar to that of ciclosporin. However, rather than binding immunophilin as does ciclosporin, tacrolimus binds to FK binding proteins in the cytoplasm. Tacrolimus has the properties (that ciclosporin does not) of interfering with IgE-receptor-dependent release of histamine and serotonin from basophils and mast cells, and it also inhibits IL-6 production.

Tacrolimus is 100 times more potently immunosuppressive than ciclosporin (Jacobson et al, 1998), but the oral bioavailability of tacrolimus is far less, and hence, the therapeutic dose of tacrolimus needed is fourfold that of ciclosporin (Package insert: Prograf (tacrolimus). Osaka, 1998).

Pharmacology of calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Ciclosporin (C62H111N11O12) is a cyclic peptide. Orally administered ciclosporin reaches peak plasma concentration in 90–120 min. The consumption of fat-containing foods 30 min before or after the administration of ciclosporin decreases the drug absorption by 13–33%. Drug elimination is carried out in the liver through P450IIIA oxidase, and the elimination half-life is dependent on the drug dose, the metabolites primarily being excreted by the bile in the faeces. (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=53787388&viewopt=PubChem#x321 assessed May 2013).

Tacrolimus (C44H69NO12) is produced from Streptomyces tsukubaensis. Orally administered tacrolimus is poorly absorbed, with an estimated final bioavailability of 17%. Concomitant food consumption further decreases drug absorption. Tacrolimus is lipophilic and is cleared from the body, after being extensively metabolized (Iwasaki, 2007), mainly by liver cytochrome P450, and excretion rates are affected by liver impairment (Venkataramanan et al, 1995). Almost all tacrolimus metabolites are excreted in the faeces. (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=445643&loc=ec_rcs#x321 accessed May 2013).

Administration and dosage of calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Ciclosporin and tacrolimus standard doses have principally been formulated for transplant patients (Table 1). For management of inflammatory diseases (e.g. rheumatoid arthritis, psoriasis), the initial recommended dose of ciclosporin is 2.5 mg kg−1 per day. Depending on the clinical response, the dose may gradually be increased up to 4 mg kg−1 per day, or if there are adverse effects, especially hypertension, it should be decreased. It is noteworthy that the two marketed ciclosporin products (Neoral and Sandimmune) are not bioequivalent, and patients should not use them interchangeably (http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050715s027,050716s028lbl.pdf, accessed May 2013). Ciclosporin is not recommended for pregnant women unless no other alternative is possible. Indications, dosage and cost of ciclosporin are summarized in Table 1.

Tacrolimus is used in combination with glucocorticoids and/or other immunosuppressants. For management of immune-mediated dermatoses, reported doses of tacrolimus used range from 0.1–0.2 mg kg−1 per day (Madan and Griffiths, 2007). Tacrolimus is often used as a second line of treatment for preventing GVHD in (graft-versus-host disease) haematological malignancies treated by haematopoietic stem cell transplantation. In a limited number of patients with severe inflammatory bowel disease, tacrolimus has produced disease improvement (Baumgart et al, 2006), and it has shown benefit in Behcet's disease with intestinal manifestations (Matsumura et al, 2010),). Tacrolimus is contraindicated in pregnancy. Indications, dosage and cost of tacrolimus are also summarized in Table 1.

Potential adverse effects of calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

The most significant adverse effects of ciclosporin are hypertension, nephrotoxicity and hepatotoxicity – hence regular monitoring includes blood pressure (BP) measuring, hepatic and renal function tests (Hoorn et al, 2012; Tedesco and Haragsim, 2012). To reduce the risk of nephrotoxicity in patients with immune-mediated diseases like psoriasis, intermittent use is preferred. It is important to note that the above adverse effects are dose dependent. Drug-induced gingival overgrowth (DIGO) is a common adverse and mainly cosmetic effect among patients who receive ciclosporin. The reported incidence of DIGO is 70% in immunosuppressed children and 25–30% in adults (Clementini et al, 2008, Dongari-Bagtzoglou, 2004,) DIGO results possibly from the inactivation of matrix metalloproteinases (Hyland et al, 2003). Gingival overgrowth may also be attributed to the co-administration of calcium channel blockers, often used for the treatment of ciclosporin-induced hypertension (Spratt et al, 1999). The gingival overgrowth is also associated with the presence of plaque and periodontal tissue inflammation; removal of these factors may improve the lesions (Aimetti et al, 2008).

A significant adverse effect of ciclosporin is an increased risk of malignancy and infections mainly concerning transplanted patients who receive a combination of potent immunosuppressive agents. Also, ciclosporin has been labelled with an FDA box warning for increased risk of skin cancer especially in patients with psoriasis who have been previously treated with PUVA (psoralen and UVA). http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050715s027,050716s028lbl.pdf accessed May 2013. Hypertrichosis (hirsutism) is also a common problem in ciclosporin, with a variable reported incidence (12.9–23%; Chugh et al, 1994; Prakash et al, 2004; Formicone et al, 2005).

Tacrolimus has a similar safety profile as ciclosporin. In addition, there is also a well-documented risk (almost tenfold in comparison with normal mean risk) of developing new onset diabetes in transplant patients treated with tacrolimus (Iida et al, 2010). This is possibly the result of the development of insulin resistance and the co-administration of glucocorticoids (Iida et al, 2010). The treatment of tacrolimus-associated diabetes is not easy and may include oral antidiabetic drugs and insulin, depending on the patient's response, but there are no specific guidelines so far (Gosmanov and Dagogo-Jack, 2012). Tacrolimus causes changes in the sympathetic outflow, which possibly result in neurotoxicity (Bechstein, 2000). Features of neurotoxicity including tremor, headache and other changes in motor and sensory function, mental status and even delirium and coma have been reported in high percentages in transplant patients treated with tacrolimus (especially after liver transplants – 55%) (http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050708s027,050709s021lbl.pdf accessed May 2013).

Of note, tacrolimus rarely causes gingival overgrowth in transplant patients (James et al, 2001), and changing medication from ciclosporin to tacrolimus has been demonstrated to resolve gingival overgrowth associated with ciclosporin (Margreiter et al, 2005).

Of interest, eight patients with solid organ transplants treated with tacrolimus presented with orofacial granulomatosis – such as oral lesions (Saalman et al, 2010). Also, although this review focuses on systemic agents, it is worth mentioning that there have been reports of malignant transformation in patients with oral lichen planus treated topically with tacrolimus (Mattsson et al, 2010).

Calcineurin inhibitors possible drug interactions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Significant drug interactions have been noted in patients taking calcineurin inhibitors with the co-administration of azoles, macrolides, rifampicin, calcium channel antagonists, grapefruit juice, St John's wort and protease inhibitors (Kuypers, 2009).

Monitoring of calcineurin inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Patients who will start ciclosporin treatment are recommended to have baseline tests with full blood count (FBC), urea and electrolytes (U&E), liver function tests (LFTs), creatinine (twice at 2 weeks apart – to obtain mean value), creatinine clearance or equivalent, and fasting lipids. Also, their BP should be <140/90 on two occasions at 2-week interval.

Periodical recommended monitoring tests are U&E including potassium and creatinine every 2 weeks until achieving stable dose and clinical outcome for 3 months and then monthly; and FBC and LFT monthly until achieving stable dose and clinical outcome for 3 months, thereafter every 3 months. Also the BP should be monitored on every patient visit. If BP is >140/90 on two consecutive visits with 2-week interval, it is advisable to treat hypertension before stopping ciclosporin (the possible interaction with anti-hypertensives are referred in the relevant section). If BP is not controlled, then the clinician should consider stopping the ciclosporin and trying to control the BP before restarting ciclosporin. Finally, periodic tests for fasting lipids are recommended.

The monitoring for tacrolimus is similar, including baseline tests with FBC, LFT, U&E, blood glucose, weight, BP, cholesterol and triglycerides, and then during treatment, the recommended tests are as follows: FBC, LF, U&E, creatinine, drug levels (especially for transplant patients), blood glucose and weight (frequency depends on clinical evaluation).

Applications of calcineurin inhibitors in oral diseases

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Although systemic ciclosporin has been proved to be an effective drug for various immune-mediated diseases, there are few publications regarding the systemic use of ciclosporin in oral diseases. In addition, the data suggest that topical ciclosporin is not particularly effective (Table 1) and, systemically, it is also nephrotoxic. Nevertheless, systemic ciclosporin has been beneficial for patients with cutaneous lichen planus and also in GVHD (Vogelsang, 2001; Madan and Griffiths, 2007). Systemic ciclosporin (or tacrolimus) is indicated for the control of patients with chronic GVHD when more than two organs are involved, and both calcineurin inhibitors have also been used for oral GVHD with variable results (Mays et al, 2013). Too few patients with oral lichen planus have been treated with systemic ciclosporin to allow conclusions (Levell et al, 1992). In pemphigus vulgaris (PV), ciclosporin has been used as a steroid-sparing agent, in high dose (5 mg kg−1) (Chrysomallis et al, 1994; Ioannides et al, 2000), but the results were not considered significant enough to allow its recommendation (Martin et al, 2011). Also, ciclosporin at a high dosage (6 mg kg−1) has been used in a small study of patients with epidermolysis bullosa acquisita (EBA) and oral lesions, with fair results (Gupta et al, 2012). Finally, ciclosporin has been also tried as a treatment for patients with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) at 3 mg kg−1 per daily for 10 days followed by gradual tapering with favourable results, but which require confirmation (Valeyrie-Allanore et al, 2010). All patients receiving systemic ciclosporin should be under close monitoring (Table 4).

Although topical tacrolimus has been used in management of various oral conditions (Al Johani et al, 2009), systemic tacrolimus is not widely used in oral medicine. The high cost of treatment (including the cost for the necessary drug monitoring) and the possible severe adverse effects discourage systemic tacrolimus use. However, systemic tacrolimus may be of help in the control of severe pemphigus (Busing et al, 2010). It is important to closely monitor all the patients on systemic tacrolimus, for drug levels and adverse effects.

Thalidomide

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Introduction

Thalidomide is widely known for its serious teratogenic effects(McBride, 1961), and the drug was withdrawn in 1961 for this reason.(Avorn, 2011) In 2012, the thalidomide story was again in the public eye attention as the company (Gruenenthal) that had launched thalidomide announced an official apology (http://www.bbc.co.uk/news/health-19448046 accessed June 2013).

Currently, a new focus has emerged on the potent anti-inflammatory properties of thalidomide (Table 2) and effects against TNF, and the drug has been approved – under close monitoring – for the treatment of multiple myeloma and erythema nodosum leprosum (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020785s048lbl.pdf accessed July 2013). It also has been used off-label for treatment of sarcoidosis, cutaneous lupus, Behcet's disease, inflammatory bowel diseases, ankylosing spondylitis, rheumatoid arthritis, chronic GVHD, cancer cachexia, HIV wasting syndrome, Kaposi sarcoma and in severe aphthous ulcers (Rehman et al, 2011).

Table 2. Thalidomide: characteristics and main clinical applications in oral diseases
Mode of actionFDA indicationsInteractionsAdverse effectsDosagesOral diseasesPrice/unit
  1. TNF, tumour necrosis factor.

Anti-TNF inhibits leucocyte migration

Anti-angiogenic

Leprosy

Multiple myeloma

Should not be administered together with anakinra or tocilizumab.

Alcohol

Barbiturates

Chlorpromazine

Birth defects

Neuropathies Venous thromboses

100–400 mg per day orally as initial dose and tapering

Aphthous ulceration

Aphthous-like ulceration

Behcet's disease

Crohn's disease

Kaposi sarcoma

Lupus erythematosus

50–100–200 mg capsules/no pricing available

For all these off-label uses, thalidomide must be administered in selected cases only and under strict control with fully informed consent (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020785s048lbl.pdf accessed July 2013).

Pharmacology of thalidomide

When administered orally, thalidomide is absorbed from the gastrointestinal tract and reaches peak plasma half-life in 2.5–6 h. Animal studies have shown that the drug is metabolized mainly in the liver, and the main urinary metabolite is a-(o-carboxybenzamido) glutarimide. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5426&loc=ec_rcs#x332

Thalidomide is a racemic product of glutamic acid. The S(−) enantiomer is a potent anti-TNF agent, and the R(+) enantiomer is responsible for the sedative effects of thalidomide (Eriksson et al, 2001).

The mechanism of the anti-inflammatory action of thalidomide is by interference with the NF-κβ transcription factor, resulting in inhibition of TNF (Chen et al, 2010). Thalidomide also has anti-angiogenic properties and alters the cytokine profile at sites of inflammation from Th1 to Th2, inhibiting the production of IL (interleukin)-6 and IL-2 as well as INFγ, and it may decrease the synthesis of basic fibroblast growth factors (Gordon and Goggin, 2003)

Thalidomide dosage and administration

Thalidomide is administered orally in a single dose before bedtime. The indicated dosages are 100–300 mg per daily for erythema nodosum leprosum and 200 mg per daily for multiple myeloma.

Thalidomide is teratogenic for females and also for males – and is strictly contraindicated for women of reproductive age as it can cause severe birth defects, even in small doses (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020785s048lbl.pdf accessed July 2013).

Thalidomide adverse events

Apart from the serious risk of teratogenicity in either gender, thalidomide has a FDA box warning for the risk of thrombosis, and it also may cause peripheral neuropathies (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020785s048lbl.pdf accessed July 2013).

In addition, thalidomide may cause somnolence, and thus, the patients are advised to take the medicine just before bedtime and to avoid other agents that may also cause sedation. Other adverse events may include constipation, bradycardia, macular rash and neutropenia (which are more common in patients with HIV; Gordon and Goggin, 2003).

Thalidomide drug interactions

Patients who are on thalidomide should avoid the use of drugs with similar adverse effect profiles. Opioids, anti-psychotics and anti-histamines should be avoided as they may potentiate the somnolence. Drugs such as beta-blockers, H2 blockers (e.g. cimetidine), anti-depressants and neuromuscular blockers should not be used as they enhance the bradycardia risk. Extra caution is required for patients with myeloma on botrezomid, as both agents may cause peripheral neuropathy.

Although women of reproductive age should not be prescribed thalidomide, in case no alternative drug is available, these women should be warned that the concomitant use of oral contraceptives and thalidomide may increase the risk of deep vein thrombosis.

Thalidomide monitoring

All patients in USA receiving thalidomide are registered in the ‘System for Thalidomide Education and Prescribing Safety (STEPS)’ and in Europe in the Thalidomide Celgene Pregnancy Prevention Programme. Female patients of reproductive age must have a negative pregnancy test 2 weeks before treatment and begin the use of oral contraceptives (Wu et al, 2005). All female patients are monitored with regular pregnancy tests during treatment, which are performed under medical personnel supervision. As it is possible for thalidomide to be found in semen, all sexually mature male patients are allowed to receive thalidomide prescription only if they are able to show understanding of the strict contraceptive measures required (including absolute avoidance of unprotected sex with women of child-bearing potential and pregnant women even if they have performed successful vasectomy). All patients should provide written consent that they have learned and understood the risks of thalidomide therapy and the required measures. Patients should be assessed by a neurologist using sensory nerve action potential tests before treatment and then at every 6 months. Patients should also be tested with FBC at regular intervals adjusted per individual patient according to their risk for neutropenia. (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000823/WC500037050.pdf accessed July 2013, http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20785lbl.pdf, accessed July 2013).

Thalidomide uses in oral diseases

Thalidomide has been proved useful in major aphthous ulceration and recurrent ulcers in HIV/AIDS and Behcet's disease (Jacobson et al, 1997; Messadi and Younai, 2010). It has been also used in a limited number of patients with oral manifestations of TNF-mediated diseases, although the number of patients is too small to permit definitive conclusions (Chen et al, 2010; Marshall, 2004) (http://pmj.bmj.com/content/79/929/127.long accessed July 2013). Also thalidomide is one of the treatment options for oral Kaposi sarcoma (Rubegni et al, 2007). In all cases, the patients should be given thalidomide with great caution and with written signed informed consent. The patients should be closely monitored for possible adverse effects. Thalidomide is a treatment choice only for some patients where other treatments have failed (Table 2), and a recent Cochrane review found little evidence of efficacy as a systemic intervention for recurrent aphthous stomatitis RAS(Brocklehurst et al, 2012).

Dapsone

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Introduction

Dapsone is a sulphone, traditionally used to treat leprosy (Doull, 1963), but it also has immunoregulating properties and has thus been used in several immune-mediated diseases, particularly in dermatitis herpetiformis (Cardones and Hall, 2012; Table 3).

Table 3. Dapsone: characteristics and main clinical applications in oral diseases
Mode of actionFDA indicationsInteractionsAdverse effectsDosagesOral diseasesPrice/unit
Folic acid antagonist interferes with polymorphonuclear cell functionsLeprosy

Anti-malarials

Rifampicin sulphonamides

Agranulocytosis

Haemolysis

Headache

Hypersensitivity reaction

Methaemoglobinaemia

50–300 mg per day for dermatitis herpetiformis. 100 mg per day for Behcet's disease

Behcet's disease

Bullous pemphigoid

Dermatitis herpetiformis

IgA pemphigus

Leprosy

Linear IgA disease

Mucous membrane pemphigoid

$143–149 for 100 tablets of 25 mg

Pharmacology of dapsone

Dapsone is an antagonist of folic acid synthesis (Wozel and Barth, 1988). A common feature of diseases that respond to dapsone is their dense infiltration with polymorphonuclear leucocytes (PMNLs; Coleman, 1993). Dapsone appears to act by inhibiting PMNL functions including chemotaxis, myeloperoxidase and lysosomal enzyme release (Wozel and Barth, 1988). Dapsone also blocks the interaction between neutrophils and epithelial basal membrane antigens in inflammatory dermatoses (Thuong-Nguyen et al, 1993).

Dapsone is usually administered orally and is rapidly absorbed, reaching peak plasma concentrations in some 2–8 h (Ellard, 1966). Approximately 70% of the drug (protein-bound and free) is distributed in all tissues, but higher concentrations are found in skin, muscles, liver and kidneys. The drug metabolism is by acetylation and hydroxylation, the latter occurring mainly in the liver via P450 cytochrome enzymes (Gill et al, 1995).

Dapsone dosage and administration

The approved uses of dapsone are for leprosy and dermatitis herpetiformis (Table 3). For leprosy, dapsone is administered at a daily dosage of 100 mg. The dapsone adult dose for dermatitis herpetiformis ranges from 50–300 mg daily. Dapsone is also popular for the treatment of neutrophilic dermatoses and bullous mucocutaneous diseases – when it is used in doses similar to those for dermatitis herpetiformis (Sago and Hall 2002).

Dapsone should be avoided in pregnant women and should be administered only if absolutely necessary (FDA pregnancy category C).

Dapsone possible adverse effects

The principal adverse effects of dapsone are haematological. Subclinical methaemoglobinaemia (plasma methaemoglobin levels under 20%) occurs in almost all patients treated with dapsone, as a result of dapsone hydroxylamine metabolites produced by hepatic and granulocytic enzymes. The production of methaemoglobin of more than 30% can cause nausea and tachycardia, while higher levels result in lethargy, altered mental functioning and even death (Ward and McCarthy, 1998). For this reason, dapsone is co-administered with cimetidine, which reduces the production of hydroxylamine (Coleman et al, 1990).

Agranulocytosis can be severe and life-threatening (Kobe et al, 2011) and is common in patients receiving dapsone for dermatitis herpetiformis, but rare in patients with leprosy.

A severe but rare (<0.5% of patients on dapsone) possible adverse event is a hypersensitivity reaction to dapsone (Lorenz et al, 2012). This syndrome manifests with fever, malaise, exanthema, lymphadenopathy and hepatitis: the laboratory findings are eosinophilia and atypical lymphocytosis. Management includes immediate drug withdrawal, symptomatic treatment and systemic steroids or immunoglobulins (Kumari et al, 2011). Hypersensitivity typically occurs in patients who receive dapsone for more than 4 weeks and most patients do recover.

Also, few cases of dapsone-induced photodermatitis have been reported, manifesting as erythema and pruritus, so patients should be advised to avoid prolonged exposure to sun (Stockel et al, 2001). Patients on dapsone may complaint of gastric upset and are thus advised to receive the drug together with food. Hepatitis both as result of cholestasis and hepatic cell destruction has been reported in dapsone patients. The alterations in hepatic function are probably dose related. A rare neurological side effect of dapsone is peripheral neuropathy, usually reversible when the drug is stopped, but rare cases of permanent optic nerve atrophy have been associated with dapsone overdosage. Finally, dapsone-associated psychotic episodes have occurred (mainly in leprosy patients). Other neurological manifestations are nervousness and headaches.

Drug interactions with dapsone

Dapsone when co-administered with other oxidative drugs such as sulphonamides and anti-malarials may cause severe haemolysis due to oxidative stress in erythrocytes. Probenecid and rifampicin may alter dapsone levels, but without significant clinical implications.

Monitoring of dapsone

Dapsone is strictly contraindicated in patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency in view of the likelihood of haemolysis: patients should thus be tested for G6PD deficiency before treatment (Pamba et al, 2012). Frequent monitoring of FBC, LFT and renal function is indicated. FBC should be performed weekly for the first month of dapsone treatment and then monthly for the first 3 months (when the risk of agranulocytosis is greatest), then at least every 3 months. Liver and renal functions should be checked every 3–6 months.

Applications of dapsone in oral diseases

Dapsone has been used in mucocutaneous diseases (Piette and Werth, 2012) and is the drug of choice for treatment of dermatitis herpetiformis. A small randomized control trial (Werth et al, 2008) and few case reports of patients exist in the literature evaluating patients with pemphigus vulgaris (PV; including patients with oral lesions). (Piette and Werth, 2011). Dapsone was used in combination with corticosteroids, and although improvements were reported, no definite conclusions could be drawn on the efficacy of dapsone for PV (Martin et al, 2011). Dapsone has show benefit for patients with cicatricial pemphigoid and epidermolysis bullosa acquisita (Zhu and Stiller, 2001). Another reported application is Behcet's disease, and in a small double-blind study focusing on mucocutaneous manifestations, 100 mg of dapsone/daily showed efficacy (Sharquie et al, 2002).

The use of dapsone is usually restricted to patients with skin and oral manifestations and often carried out in collaboration with a dermatologist. The main features of dapsone are summarized in Table 3.

Colchicine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Colchicine is an alkaloid isolated from Colchicum autumnaleit and acts by binding to tubulin in microtubules to block mitosis – mainly in neutrophils – thereby inhibiting their mobility and activity (Molad, 2002). Colchicine also inhibits leukotriene B4 and interferes with inflammasome formations both in granulocytes and monocytes (Molad, 2002).

Colchicine is traditionally used in management of acute gout and familial Mediterranean fever (FMF; Hamburger et al, 2011; http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022352s004lbl.pdf accessed July 2013) and is often used in auto-inflammatory states (Scully et al, 2008; Table 4).

Table 4. Colchicine: characteristics and main clinical applications in oral diseases
Mode of actionFDA indicationsInteractionsAdverse effectsDosagesOral diseasesPrice/unit
Inhibits mitosis and inflammasome

Acute gout flares

Familial Mediterranean fever

CYP3A4 inhibitors sulphonamides

Azoospermia or oligospermia Diarrhoea

Hepatic impairment

Nausea or vomiting

Renal impairment

1.8 mg maximum dose/day for acute gout 1–2 mg per day for Behcet's disease

Aphthous ulceration

Auto-inflammatory diseases

Behcet's disease

$ 69.46 for 100 tablets 0.6 mg

Pharmacology of colchicine

Colchicine is administered orally, and the absorption from the gastrointestinal tract is variable, the drug reaching peak plasma concentrations within two hours. The drug is deacetylated in the liver and excreted in bile and urine. The enterohepatic circulation is considered responsible for the gastrointestinal irritation commonly experienced by patients receiving colchicine.

Colchicine is contraindicated for patients with renal or hepatic disease, and it should not be co-administered with any drugs that inhibit the CYP3A4 enzyme.

Dosage and administration of colchicine

Acute gout flares and FMF are the FDA indications for colchicine use. The recommended dosage is then 1.8 mg maximum/day for acute gout, FMF-related amyloidosis and other auto-inflammatory diseases.

Adverse effects of colchicine

Common adverse effects of colchicine are from the gastrointestinal tract (diarrhoea, nausea, vomiting; http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022352s004lbl.pdf accessed July 2013). Myopathy or rhabdomyolysis may manifest as muscular atrophy, may be accompanied by elevation of creatine kinase and may also coexist with neuropathy. Other less common but more severe adverse effects include leukopenia and hepatotoxicity. Alopecia and hair loss reversible upon discontinuation of the drug have been reported. In cases of severe colchicine toxicity, patients may present with dysuria, haematuria, proteinuria, intestinal ileus and bone marrow suppression.

Colchicine use is contraindicated in patients with severe hepatic disease. It may be used in children only if they are older than 4 years and may be administered to pregnant women if unavoidable (category C). Male patients should be also warned of possible oligospermia or azoospermia (http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022352s004lbl.pdf accessed July 2013).

Drug interactions with colchicine

The most significant drug interaction of colchicine is the risk of neuropathy and neuromyopathy from the combination with ciclosporin (Rana et al, 1997). Also, there is risk of toxicity from concomitant use of inhibitors of CYP3A4 or P-glycoprotein, when doses should be reduced (Terkeltaub et al, 2011).

Monitoring of colchicine

Patients on colchicine rarely require continuous clinical monitoring, but if the patients complain of weakness, blood creatine kinase levels should be checked (Ly et al, 2007).

Colchicine application in oral diseases

Colchicine has been of some value in managing oral ulceration in Behcet's disease and recurrent aphthous stomatitis (Ruah et al, 1988; Yurdakul et al, 2001; Brocklehurst et al, 2012) and is the main treatment for ulceration in auto-inflammatory states (Scully et al, 2008). Of note, the response of patients with Behcet's disease to colchicine is one of the facts that strengthen the hypothesis that Behcet is an auto-inflammatory rather than autoimmune disease (Pineton de Chambrun et al, 2012). Colchicine may be a rather safe choice for patients with persistent aphthae and aphthous such as ulcers, although its use requires further validation.

The main features of colchicine are summarized in Table 4.

Cyclophosphamide

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References

Introduction

Cyclophosphamide is a chemotherapy agent with significant uses in diseases with autoimmune and inflammatory pathogeneses (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013; Table 5).

Table 5. Cyclophosphamide: characteristics and main clinical applications in oral diseases
Mode of actionIndicationsInteractionsMain adverse effectsDosagesOral diseasesPrice/unit
Alkylating agent

FDA-approved

Malignancies

Nephrotic syndrome

Off-label

Vasculitis

Lupus nephritis

Etanercept

Live adenovirus vaccines

Phenobarbital

Succinylcholine chloride

Haemorrhagic cystitis Infections

Infertility

Malignancies

Malignant diseases: 40–50 mg kg−1 IV over a period of 2–5 days

Orally: 1–5 mg kg−1 per day

Nephrotic syndrome: 2.5–3 mg kg−1 daily

Pemphigus vulgaris

Wegener vasculitis

$78–85/vial

Cyclophosphamide pharmacology

When administered orally in the usual doses for inflammatory diseases (1–5 mg kg−1 per day), the absorption of cyclophosphamide is variable and the metabolism is by the liver microsomal enzymes. Cyclophosphamide metabolites inhibit cellular replication via alkylation of the N' of guanine in DNA, which leads to miscoding, damage to the purine ring construction of guanine (depurination) and DNA cross-linking. Cyclophosphamide action is mainly on rapidly proliferating cells, and hence, cyclophosphamide causes depletion of peripheral B and T lymphocytes, suppressing cell-mediated immunity and antibody production.

Cyclophosphamide administration and dosage

The principal use of cyclophosphamide is for the treatment of malignant neoplasms, but it is used also in various immune-mediated diseases. It is the main drug used for the treatment of Wegener granulomatosis (granulomatosis with polyangiitis), when it is usually used in combination with corticosteroids (Manna et al, 2008). Cyclophosphamide has also been effective in treating other vasculitides (polyarteritis nodosa, microscopic polyangiitis, Churg–Strauss syndrome, cryoglobulinaemia, central nervous system vasculitis, rheumatoid vasculitis; Mukhtyar et al, 2009). Cyclophosphamide has also been used with success in the treatment of connective tissue diseases such as lupus erythematosus (Martin-Suarez et al, 1997) and, as a steroid-sparing agent, in severe pemphigus – when the effectiveness is comparable with azathioprine (Martin et al, 2011). The dosage for inflammatory diseases is 1–5 mg kg−1 per day.

Adverse effects of cyclophosphamide

Adverse effects of cyclophosphamide include the risk of infections and certain types of solid and haematological malignancies (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013).

The probability and severity of these and other adverse effects of cyclophosphamide depend on the route of administration [IV (higher) or oral], the dose and the duration of treatment. Cyclophosphamide increases the risk of opportunistic infections including candidosis, Pneumocystis carinii (jiroveci) pneumonia and human papillomavirus infections. Cyclophosphamide may also cause bone marrow suppression: both IV and oral administration produce low white blood cell counts after 1–2 weeks of treatment. The patients' FBC must therefore be monitored every 2–4 weeks throughout treatment. Of note, however, is that a fall in white cell count to 2000–3000 may occur without significantly increasing the risk for infections (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013).

Patients who use cyclophosphamide for a prolonged period are at increased risk of developing malignancies in bone marrow, lymph nodes and especially bladder (Talar-Williams et al, 1996). The risk of bladder cancer is greater for patients who receive cyclophosphamide orally. The reported risk and projected 15 years of incidences for the development of bladder cancer among patients with Wegener granulomatosis treated with cyclophosphamide are 6% and 16%, respectively (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013).

Chronic use of cyclophosphamide may also cause bleeding from the bladder, the severity ranging from microscopic haematuria to haemorrhagic cystitis, which can be life-threatening (Talar-Williams et al, 1996). The IV administration of cyclophosphamide combined with the protective organosulphur compound MESNA may reduce bladder toxicity (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013).

Another important adverse effect of cyclophosphamide is infertility, an effect that is dose and time dependent and seen in both genders. The risk is greatest in female patients who are over thirty years of age when they begin treatment (Clowse et al, 2011).

Drug interactions of cyclophosphamide

Cyclophosphamide may show increased myelotoxicity risk when combined with other cytotoxic agents. The co-administration with phenobarbitone may increase the metabolism of cyclophosphamide. Anaesthesiologists should be aware that cyclophosphamide may increase the effect of succinyl choline chloride. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/012141s089lbl.pdf accessed July 2013.

Monitoring of cyclophosphamide

Patients on cyclophosphamide require close monitoring. Prior to beginning treatment, patients should have a baseline complete FBC, liver function, U&E, glomerular filtration rate (GFR), erythrocyte sedimentation rate, C-reactive protein and urinalysis. For the first 4 weeks, patients should be checked with FBC, LFT, U&E, GFR weekly, then every 2 weeks for 8 weeks and thereafter monthly. Urinalysis should be performed monthly. If there is a drop of >20% in GFR, patients should have a nephrological opinion.

Application of cyclophosphamide in oral diseases

The main application of cyclophosphamide in oral diseases is in PV unresponsive to corticosteroid monotherapy and other immunoregulating agents. A recent meta-analysis showed a significant steroid-sparing effect superior to that of mycophenolate, but inferior to azathioprine.(Martin et al, 2011) Cyclophosphamide has also been used for patients with Wegener granulomatosis with oral lesions (Almouhawis et al, 2013). The main features of cyclophopsphamide are summarized in Table 5.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Calcineurin inhibitors
  5. Pharmacology of calcineurin inhibitors
  6. Administration and dosage of calcineurin inhibitors
  7. Potential adverse effects of calcineurin inhibitors
  8. Calcineurin inhibitors possible drug interactions
  9. Monitoring of calcineurin inhibitors
  10. Applications of calcineurin inhibitors in oral diseases
  11. Thalidomide
  12. Dapsone
  13. Colchicine
  14. Cyclophosphamide
  15. Author contributions
  16. References